Oral non-combusted tobacco products have the greatest likelihood of leading to harm reduction compared to other potential reduced exposure products (Gray et al., 2005; Hatsukami & Hecht, 2005). Tobacco companies have been developing and marketing oral tobacco products that appeal to cigarette smokers as a substitute for cigarettes. Some public health researchers believe that switching smokers to oral tobacco would lead to a significant reduction in mortality and morbidity and point to data showing significantly less health risk with smokeless tobacco use compared to cigarette smoking. However, very little research has examined if smokers in the US will find oral tobacco products palatable as a cessation aid, the toxicity of these products compared to cigarettes as assessed by biomarkers of exposure and toxicity in humans, and whether or not use of these products will result in significant smoking cessation rates, particularly compared to FDA approved cessation products, such as medicinal nicotine. This proposal describes two studies which will be the first systematic effort to address these questions. The first study will determine the palatability and preference of various oral non-combusted tobacco products in cigarette smokers, which will inform the product to be tested in Study 2. Smokers will be presented with four brands of oral tobacco that are all low in tobacco specific nitrosamine levels but vary in nicotine content and product type. Subjects will sequentially, and in randomized order, sample each of these products and at the end of the sampling period, choose which product that they would like to use during a subsequent 4-week abstinence from smoking. The main outcome measure will be determining the product that is most preferred, which will then be used in the subsequent clinical trial. Other outcome measures include pattern of product use, subjective and physiological responses to the product, withdrawal symptoms from the product and biomarkers of exposure and toxicity. The second study will be a randomized clinical trial comparing the efficacy of an oral tobacco product compared to a medicinal nicotine product for smokers wishing to quit. Subjects will be randomized to either the most preferred oral tobacco product determined in Study 1 or nicotine gum for a period of 12 weeks. Follow-up will occur at 26 and 52 weeks. The primary outcome variables are abstinence rates across the two products, extent of cigarette reduction in non-abstainers and continued product use after the end of treatment. Other outcome variables are similar to the first study. A cost analysis will be conducted if the oral tobacco product is similar to or exceeds the cessation rates of medicinal nicotine. The results from these studies will help determine the effects and feasibility of using oral tobacco products as both a cessation aid and a method to reduce individual health risk in cigarette smokers.